Substituted phenoxymalonic acids, esters thereof and hypolipaemic agents containing the same for lowering lipid levels

ABSTRACT

Compounds of the general formula wherein R1 is a halogen, alkyl, alkoxy, CF3 or alkyl sulphonyl group, wherein R2 and R3 are hydrogen or halogen, alkyl, alkoxy, CF3 or alkyl sulphonyl groups, wherein R4 and R6 are hydrogen or alkyl groups and wherein R5 is an alkyl group. The compounds are useful as hypolipaemic agents.

United States Patent [191 Barthold et al.

[73] Assignee: Astra Lakemedel Aktiebolag,

Sodertalje, Sweden [22] Filed: Oct. 16, 1973 [21] Appl. No.: 406,920

[30] Foreign Application Priority Data Nov. 1,1972 Sweden 14117/72 [52]US. Cl. 424/308; 260/473 G; 260/470; 260/521; 424/303; 424/317 [51] Int.Cl. ..A61K 31/19; A61K3l/235; A61K 3 1/255 [58] Field of Search 424/308,317

[56] References Cited UNITED STATES PATENTS 10/1969 Griot 424/308 3/1971Cavalleri et a1 424/308 Dec. 23, 1975 OTHER PUBLICATIONS ChemicalAbstracts 73:65979c (1970).-

Primary Examiner-Stanley J. Friedman Attorney, Agent, or FirmBrumbaugh,Graves, Donohue & Raymond 57 ABSTRACT Compounds of the general formulawherein R is a halogen, alkyl, alkoxy, CF 3 or alkyl sulphonyl group,wherein R and R are hydrogen or halogen, alkyl, alkoxy, CF or alkylsulphonyl groups, wherein R and R are hydrogen or alkyl groups andwherein R is an alkyl group. The compounds are useful as hypolipaemicagents.

26 Claims, N0 Drawings SUBSTITUTED PHENOXYMALONIC ACIDS, ESTERS THEREOFAND HYPOLIPAEMIC AGENTS CONTAINING THE SAME FOR LOWERING LIPID LEVELSFIELD OF INVENTION The present invention relates to compounds havingvaluable therapeutical properties particularly as hypolipemic agents,and therapeutically acceptable salts thereof. The invention also relatesto methods for the preparation of the compounds, to pharmaceuticalpreparations containing them and to a method for the treatment ofcertain diseases by administering a therapeutically effective amount ofa compound of the invention in association with a pharmaceuticallyacceptable carrier.

BACKGROUND OF INVENTION In view of accumulating evidence indicating thatexcessive serum lipid concentration is correlated to .basic pathogeneticmechanisms and to symptoms of several diseases such as vasculardiseases, diabetes mellitus, and hyperthyroidism, lowering of serumlipid concentration is important during treatment of such diseases. i

A compound used for the treatment of hyperlipemia isethyl-alp-chlorophenoxy)isobutyrate, which compound is also namedAtromidin. This compound, however, suffers from the disadvantage ofgiving only a minor decrease of the cholesterol concentration.Pharmaceuticals with ability to decrease cholesterol levels in mammalsincluding man are known, but because of the possible complicationsinvolved in simultaneous administration of two different drugs it wouldbe of great advantage to use a compound with the ability to give acombined lowering of both cholesterol and triglyceride concentration.The main object of the pres ent invention is to provide compounds withsuch beneficial properties of lowering both cholesterol levels andtriglyceride levels in mammals including man. Another object of theinvention is to provide compounds which have a lowering effect on theserum level of triglycerides in mammals including man.

DETAILED DESCRIPTION OF INVENTION According to the present invention ithas surprisingly been found, that compounds of the general formula OOR6and therapeutically acceptable salts thereof, in which formula R, isselected from the group consisting of halogen such as F, Cl, Br and I,alkyl groups containing 2 selected from the group consisting of H,halogen such as F, Cl, Br and I, alkyl groups containing from 1 to 4carbon atoms alkoxy groups containing from 1 to 4 carbon atoms, CF andalkyl sulphonyl groups containing from 1 to 3 carbon atoms in the'alkylgroup; wherein R and R are the same or different and selected from thegroup consisting of hydrogen and alkyl groups containing from I to 4carbon atoms; and wherein R is an alkyl group containing from 1 to'4carbon atoms; can be used for lowering of serum triglycerideconcentrations in animals including man, and that certain compoundsincluded in the formula I give a combined lowering of both serumcholesterol and serum triglycerides. Any of the radicals R, R and R iomaonomu- -wtvmu-Jsuio The compounds of the formulas and are thepreferred compounds of the invention because of their capability tolower simultaneously serum levels of cholesterol and triglycerides.

The compounds according to the present invention are prepared in mannerknown per se by reacting a compound of the formula OH IV in whichformula R, R and R have the meaning specified above, with ana-alkylmalonic acid ester of the formula 2 R R I COD-R O -R" Vl OO-R 3are replaced by hydrogen by hydrolysing the compound of the formula VIin manner known per se.

It is necessary that the carboxyl groups are protected by esterificationduring the reaction between the compound of the formula IV and thecompound of the formula V.

Examples of reactive groups X are Cl, Br, I, parato luensulphonyloxy,and methylsulphonyloxy. The reaction is preferably carried out inpresence ofa base such as alkali alkoxides, alkali carbonates, alkalihydrides, alkali amides.

Compounds of the formula I wherein one or both of the radicals R and Rare hydrogen can be converted into salts by reaction with an appropriatebase. Examples of salts of said acids are the alkali metal or alkalineearth metal salts such as the sodium, potassium or calcium salts.

In clinical practice the compounds of the present invention willnormally be administered orally or by injection in the form of apharmaceutical preparation comprising the active ingredient in the formof the original compound or optionally in the form of a pharmaceuticallyacceptable salt thereof, in association with a pharmaceuticallyacceptable carrier which may be a solid, semi-solid or liquid diluent oran ingestibel capsule, and such preparations comprise a further aspectof the invention. Usually the active substance will comprise between 0,]and percent by weight of the preparation, for example between 0,5 and 20percent for preparations intended for injection and between 0.1 and 50percent for preparations intended for oral administration.

the active ingredient may be mixed with a solid, pulverulent carrier,for example lactose, saccharose, sorbitol, mannitol, a starch such aspotato starch, corn starch, amylopectin, laminaria powder or citrus pulppowder, a

cellulose derivative or gelatine, and also may include lubricants suchas magnesium or calcium stearate or a Carbowax or polyethylene glycolsand compressed to form tablets or centers for dragees. lf dragees arerequired, the centers may be coated, for example with concentrated sugarsolutions which may contain gum arabic, talc and/or titanium dioxide, oralternatively with a lacquer dissolved in easily volatile organicsolvents or mixtures of organic solvents. Dyestuffs can be added tothese coatings, for example, to distinguish between different contentsof active substance. For the preparation of soft gelatine capsules(pearl-shaped closed capsules) consisting of gelatine and, for example,glycerol, or similar closed capsules, the active substance may beadmixed with a Carbowax. Hard gelatine capsules may contain granulatesof the active substance with solid, pulverulent carriers such aslactose, saccharose, sorbitol, mannitol, starches (for example potatostarch, corn starch or amylopectin), cellulose derivatives or gelatine,and may also include magnesium stearate or stearic acid.

Liquid preparations for oral application may be in the form of syrups orsuspensions, for example solutions containing from about 0.1 to 20percent by weight of active substance, sugar and a mixture of ethanol,water, glycerol, propyleneglycol and optionally, aroma, saccharineand/or a dispersing agent such as carboxymethyl cellulose.

For parenteral application by injection preparations may comprise anaqueous solution of a water soluble pharmaceutically acceptable salt ofthe active substance desirably in a concentration of 0.5- percent andoptionally also a stabilizing agent and/or buffer substance in aqueoussolution, and NaCl to make the solution isotonic. Dosage units of thesolution may advantageously be enclosed in ampoules.

The dosage used is dependent on individual requirements but theadministration of about 0.1-1 g of the active substance 1-2 times a daymay be used as therapeutical treatment of hyperlipaemia in man. The saiddosage is primarily intended for oral administra- 6 EXAMPLE 2 In amanner analogous with that described in example 1 compounds of theformula were prepared. The physical data of the compounds are given inTable 1 below. For completeness also the compound prepared in Example 1is included.

TABLE I.

Physical data for compounds according to the invention tion.

.p. Compound No. R R R "C (mm Hg) 1 Z-CH; H H 121-122 (0.5) 2 3-CH H H128-129 (0.8) 3 4-CH H H 122-123 (0.2) 4 2-Cl H H 129-130 (0.4) 5 4-Cl HH 123-124 (0.2) 6 3-1 H H 141-142 (0.5) 7 4-1 H H 141-142 (0.4) 8 2-OCHH H 138-139 (0.8) 9 3-OCH; H H 135-136 (0.4) 10 4-CF H H 140-142 (0.4)11 (PC)4- H H 145-146 (0.3)

CH SO 12 2-CH 3-CH H 137-138 (1.1) 13 Z-CH; H 4-CH; 118-119 (0.4) 142-CH H S-CH 122-123 (0.6) 15 3-CH H 4-CH 130-131 (0.4) 16 3-CH H 5-CH;,119-120 (0.4) 17 2-Cl H 6-CH; 138-139 (0.5) 18 Z-CH; H 4-Cl 119-120(0.3) 19 3-CH 4-Cl H 122-123 (0.4) 20 Z-CH H 4-F 135-136 (0.5) 21 2-Cl4-Cl H 135-136 (0.4)

EXAMPLE 3 The following examples are intended solely to illustrate theinvention and should not be construed as limiting the scope of theclaims in any way.

EXAMPLE 1 Preparation of a-(4-chloro-2-methylphenoxy)-a-methyl-malonicacid diethylester To a solution of 0.1 mole of 4-chloro-2-metylphenol in90 ml acetone and 10 ml toluene was added under stirring 0.1 1 molepotassium carbonate and thereafter dropwise 0.12 molea-chloro-a-methyl-malonic diethylester. The reaction mixture was boiledunder stirring for 24 hours. After filtering the solvent was evaporated,ml toluene was added and the toluene phase was washed with 90 NaOH (4X25ml) and water (4X25 ml). The organic phase was dried over magnesiumsulphate. After filtering the solvent was removed in vacuum and theremainder distilled in vacuum. The product obtained,a-(4-chloro-2-methylphenoxy)-amethyl-malonic acid diethylester had aboiling point of l l9120C at a pressure of 0.3 mm Hg. The refractionindex n was 1.4962. Yield: 59 percent.

Preparation of a-(4-chlorophenoxy)-a-methyl-malonic acid dimethylesterTo a solution of 01 moles 4-chlorophenol in ml acetone and 25 m1 toluenewas added 0.1 mole sodiummethoxide and the mixture was stirred at roomtemperature for 1 hour. Thereafter 0.12 mole ofa-(ptoluenesulphonyloxy)-oz-methyl-malonic acid dimethylester was addedin small portions, whereafter the mixture was boiled under reflux for 24hours. The reaction mixture was worked up in the same way as describedin Example 1. The product had a boiling point of 127-128C at a pressureof 0.3 mm Hg. The refraktion index n was 1.4980. Yield: 48 percent.

The following examples illustrate how the compound of the invention canbe incorporated in pharmaceutical compositions, in which examples theactive substance is exemplified by the preferred compounds.

EXAMPLE 4 Preparation of soft gelatine capsules 500 g ofoz-(4-chloro-2-methylphenoxy)-a-methyltine capsules, eachcapsule'containing 100 mg of the mixture (i.e. 50 mg of activesubstance).

EXAMPLE Preparation of soft gelatine capsules 500 g ofa-(4-chloro-2-methylphenoxy)-a-methylmalonic acid diethyl ester weremixed with 750 g of peanut oil whereafter the mixture was filled in softgelatine capsules, each capsule containing 125 mg of the mixture (i.e.50 mg of active substance).

EXAMPLE 6 Preparation of tablets 5 kg ofa-(4-chloro-2-methylphenoxy)-a-methylmalonic acid diethyl ester weremixed with 2 kg of silicon dioxide of the trademark Aerosil, whereafter4.5 kg of potato starch and 5 kg of lactose were mixed in and themixture moistened with a starch paste prepared from 0.5 kg of potatostarch and distilled water, whereafter the mixture was granulatedthrough a sieve. The granulate was dried and sieved whereafter 0.2 kg ofmagnesium stearate were mixed in. Finally the mixture was pressed intotablets, each weighing 172 mg.

EXAMPLE 7 Preparation of an emulsion 100 g ofa-(4-chloro-2-methylphenoxy)-a-methylmalonic acid diethyl ester weredissolved in 2500 g of peanut oil. From the solution thus obtained, 90 gof gum arabic, aroma and colour (q.s.) and 2500 g of water an emulsionwas prepared.

EXAMPLE 8 Preparation of a syrup 100 g ofa-(4-chloro-2-methylphenoxy)-a-methylmalonic acid diethyl ester weredissolved in 300 g of 95 ethanol where 300 g of glycerol, aroma andcolour (q.s.) and water 1000 ml were mixed in. A syrup was thusobtained.

EXAMPLE 9 Preparation of a solution 100 g ofa-(4-iodophenoxy)-a-methylmalonic acid diethyl ester were dissolved in2000 g of polyoxyethylene sorbitan monooleate, whereafter aroma andcolour (q.s.) and water to 5000 ml were mixed in. A drop solution wasthus obtained.

EXAMPLE 10 Preparation of effervescent tablets 100 g ofa-(4-chloro-2-methylphenoxy)-a-methylmalonic acid diethyl ester 140 g ofpowdered citric acid, 1 10 g of powdered sodium hydrogen carbonate, 3.5g of magnesium stearate and aroma (q.s.) were mixed and the mixture waspressed into tablets, each containing 100 mg of active substance.

EXAMPLE 11 Preparation of a drop solution 100 g ofa-(4-chloro-2-methylphenoxy)-a-methyl' malonic acid diethyl ester weremixed with 300 g of ethanol, whereafter 300 g of glycerol, water to 1000ml aroma and colour (q.s) and 0.1 N sodium hydroxide solution (to pH4.5-5.5) were added while stirring. A drop solution was thus obtained.

EXAMPLE 12 Preparation of a sustained release tablet 200 g ofa-(4-iodophenoxy)-a-methylmalonic acid diethyl ester were meltedtogether with 50 g of stearic acid and 50 g of carnauba wax. The mixturethus obtained was cooled and ground to a particle size of maximum 1 mm.The mass thus obtained was mixed with 5 g of magnesium stearate andpressed into tablets each weighing 305 mg. Each tablet thus contains 200mg of active substance.

BIOLOGICAL TESTS A. Effect on the level of cholesterol and triglyceridesin mouse plasma Male mice of the N.M.R.l. strain with bodyweights of20-22 g were fed ground mouse chow supplemented with test substances(0.15-0.3 w/w) for 6 days. Twelve mice forming one group were housed inthe same cage. For each test group one group simultaneously served ascontrol. At the end of the experiment the mice were decapitated andblood from 3 mice was pooled for the determination of cholesterol andtriglycerides.

Analysis of plasma lipids Total cholesterol and triglycerides weredetermined by methods from Technicon for Autoanalyzer, described inTechnicon Laboratory Method File no. 24a resp. no. 78.

Diet

The mice were fed commercial mouse chow obtained from Astra-Ewes,Sodertalje, Sweden. The control group received mouse chow with noaddition of active compounds.

Results The results are collected in Table 11 below. All compoundsreduce the level of triglycerides in plasma, and the compounds 2, 7 and18 also lower the cholesterol level.

The cholesterol and triglyceride values in the control groups varybetween 141 and 182 mg/100 ml and between 1.00 and 1.88 umole/mlrespectively. These fluctuations are mainly due to seasonal variationsduring the course of the tests which extended for a period of more than18 months.

The food intakes were measured indirectly by observing the change ofbody weight during the experiment. No difference could be observedbetween the test groups and control groups.

TABLE II Plasma levels of total cholesterol and triglycerides afteradministration of test substance.

Total Cholesterol Triglycerides Test Control Ratio Test Control RatioAverage weight gain (g) Compound Per cent group roup test/control groupgroup test/control per animal after 6 days (numbered test substancemg/lOO ml mg/100 ml (percent) umole/ml umole/ml (percent) Test Controlas in Ex. 2) in diet plasma plasma plasma plasma group group 1 0.2 176:715915 111 0.621006 1.211022 51 2 2 2 0.15 147:4 l59fi 93 07310.0412110.22 l 2 Plasma levels of total cholesterol and triglycerides afteradministration of test substance.

Total Cholesterol Triglycerides Test Control Ratio Test Control RatioAverage weight gain (g) Compound Per cent group group test/control groupgroup I test/control per animal after 6 days (numbered test substancemg/ 100 ml mg/ 100 ml (percent) pmole/ml umole/ml (percent) Test Controlas in Ex. 2) in diet plasma plasma plasma plasma group I group 3 0.318313 14818 123 1.151009 1.881008 61 2 3 4 03 15916 15113 105 1.3210101.491008 89 3 3 5 03 15113 15113 100 0610.10 1.491008 71 2 3 6 0.3189110 18014 105 0.551002 1.001010 55 l 2 7 0.3 15115 ISES 83 09910.071.271010 78 2 3 8 0.2 17619 16913 104 1.071010 1.401006 76 3 2 9 0.316018 16113 100 0.711009 1.111018 64 2 2 12 0.3 19714 169B 117 0.9910071.401006 71 2 2 13 0.3 18915 18218 104 0.781003 1.271010 61 3 3 14 0.317617 159$ 104 0.791005 1.211022 56 l 2 15 0.3 17015 15915 107 0.5710071.211022 47 2 2 16 0.3 16113 15613 104 06610.08 1.191010 55 4 3 17 0.315617 15613 100 0.751005 1.191010 63 3 3 18 0.3 12213 16113 76 0.5510091.111018 50 l 2 19 0.3 15516 16113 96 0.631008 1.111018 57 1 2 21 0.3162fl 14117 115 0.631007 1.261010 50 2 3 Atromid 0.3 173 163 106 0.631.34 47 2 3 (mean of 10 tests) B. Effect on the level of cholesterol andtriglycerides in 25 R rat plasma Male rats of the Sprague-Dawley strainwith a level of 5 total cholesterol exceeding 180 mg per 100 ml plasma Owere used. Each group consisted of 6 rats. The rats 00k were fed a dietsupplemented with test substance, 0.3 w/w, for 6 days. Blood sampleswere taken immediately before the start of the experiment and after 6days. The samples were taken by the morbital eye technique, i.e. out ofthe ophthalmic venous complex, without sacrificing the animals. Theindividual rats could thus serve as their own controls.

Diet

The rats were fed commercial rat chow obtained from Astra-Ewes,Sodertalje, Sweden, ground and supplemented with the test substances.

Results The results are collected in Table 111 below. All compoundstested reduce the plasma levels of cholesterol and triglycerides,compounds 7 and 18 being more active than Atromid.

Table 111 Plasma levels of total cholesterol and triglycerides afteradministration of test substance Com ound Total cholesterol in of 0.initial values (day 0) Trigl cerides in of mitia values (day 0) 2 91 1 389 1 5 3 92 1 9 78 1 6 7 631 5 52 1 6 18 71 1 3 37 1 5 Atromid 76 66(mean of 3 tests) or a therapeutically acceptable salt thereof, whereinR is selected from the group consisting of halogen, alkyl groupscontaining from 1 to 4 carbon atoms, alkoxy groups containing 1 to 4carbon atoms, and trifluoromethyl; R and R are the same or different andare selected from the group consisting of hydrogen, halogen, alkylgroups containing from 1 to 4 carbon atoms, alkoxy groups containingfrom 1 to 4 carbon atoms, and trifluoromethyl; R and R are the same ordifferent and are selected from the group consisting of hydrogen andalkyl containing from 1 to 4 carbon atoms; and R is an alkyl groupcontaining from 1 to 4 carbon atoms, in association with apharmaceutically acceptable carrier.

2. A method according to claim 1 wherein R, R and R are the same ordifferent and are selected from the group consisting of C1 1, F, CH, OCHand CF 3. A method according to claim 2 wherein R and R are both C 11and R is CH 4. A method according to claim 3 wherein R methyl and R andR are hydrogen.

5. A method according to claim 3 wherein R methyl and R and R arehydrogen.

6. A method according to claim 3 wherein R is 4- methyl and R and R arehydrogen.

7. A method according to claim 3 wherein R chloro and R and R arehydrogen.

8. A method according to claim 3 wherein R is 4- chloro and R and R arehydrogen.

9. A method according to claim 3 wherein R iodo and R and R arehydrogen.

10. A method according to claim 3 wherein R is 4-iodo and R and R arehydrogen.

11. A method according to claim 3 wherein R is Z-methoxy and R and R arehydrogen.

1 l 12. A method according to claim 3 wherein 3-methoxy and R and R arehydrogen.

13. A method according to claim 3 wherein 4-trifluoromethyl and R and Rare hydrogen.

14. A method according to claim 3 wherein Z-methyl, R is 3-methyl, and Ris hydrogen.

15. A method according to claim 3 wherein 2-methyl, R is hydrogen, and Ris 4-methyl.

16. A method according to claim 3 wherein 2-methyl, R is hydrogen, and Ris 5-methyl.

17. A method according to claim 3 wherein 3-methyl, R is hydrogen, and Ris 4-methyl.

18. A method according to claim 3 wherein 3-methyl, R is hydrogen, and Ris S-methyl.

19. A method according to claim 3 wherein 2-chloro, R is hydrogen, and Ris 6-methyl.

20. A method according to claim 3 wherein 2-methyl, R is hydrogen, and Ris 4-chloro.

21. A method according to claim 3 wherein 3-methyl, R is 4-chloro, and Ris hydrogen.

22. A method according to claim 3 wherein Z-methyl, R is hydrogen, and Ris 4-fluoro.

23. A method according to claim 3 wherein 2-chloro, R is 4-chloro, and Ris hydrogen.

24. A method for lowering the serum level of triglycerides in animalsincluding man, characterized in administration to a host in need of suchtreatment a thera- 12 peutically effective amount of a pharmaceuticalpreparation according to claim 1.

25. A method for lowering the serum level of cholesterol in animalsincluding man, characterized in administration to a host in need of suchtreatment a therapeutically effective amount of a pharmaceuticalpreparation according to claim 1.

26. A method for lowering the serum levels of triglycerides andcholesterol in animals including man, comprising administration to aanimal host in need of said treatment a therapeutically effective amountof a compound selected from the group consisting of and COOC H CIO-i-CH,

OOC H UNITED STATES PATENT AND TRADEMARK OFFICE fiERTlFMATE 0FCORRECTION PATENT NO. 3,928,602 DATED December 23, 1975 ]N\/ENTOR(S) DAGVILHELM BARTHOLD, et a1 It is certified that error appears in theab0veidentified patent and that said Letters Patent are hereby correctedas shown below:

Column 10, line 50, "C1 should read -Cland "CH" should read -CH Signedand Sealed this RU?" C. MASON- C. MARSHALL DANN V Alluring OfficerCommissioner nj'lan'nls and Trademarks

1. A METHOD FOR LOWERING SERUM LIPID CCONCENTRATION IN ANIMALS,INCLUDING MAN, WHICH COMPRISES ADMINISTERING TO AN ANIMAL IN NEED OFSUCH TREATMENT, AS THE ACTIVE INGREDIENT, A THEREAPEUTICALLY EFFECTIVEAMOUNT OF A COMPOUND OF THE FORMULA
 2. A method according to claim 1wherein R1, R2, and R3 are the same or different and are selected fromthe group consisting of Cl3, I, F, CH, OCH3, and CF3.
 3. A methodaccording to claim 2 wherein R4 and R6 are both C2H5 and R5 is CH3.
 4. Amethod according to claim 3 wherein R1 is 2-methyl and R2 and R3 arehydrogen.
 5. A method according to claim 3 wherein R1 is 3-methyl and R2and R3 are hydrogen.
 6. A method according to claim 3 wherein R1 is4-methyl and R2 and R3 are hydrogen.
 7. A method according to claim 3wherein R1 is 2-chloro and R2 and R3 are hydrogen.
 8. A method accordingto claim 3 wherein R1 is 4-chloro and R2 and R3 are hydrogen.
 9. Amethod according to claim 3 wherein R1 is 3-iodo and R2 and R3 arehydrogen.
 10. A method according to claim 3 wherein R1 is 4-iodo and R2and R3 are hydrogen.
 11. A method according to clAim 3 wherein R1 is2-methoxy and R2 and R3 are hydrogen.
 12. A method according to claim 3wherein R1 is 3-methoxy and R2 and R3 are hydrogen.
 13. A methodaccording to claim 3 wherein R1 is 4-trifluoromethyl and R2 and R3 arehydrogen.
 14. A method according to claim 3 wherein R1 is 2-methyl, R2is 3-methyl, and R3 is hydrogen.
 15. A method according to claim 3wherein R1 is 2-methyl, R2 is hydrogen, and R3 is 4-methyl.
 16. A methodaccording to claim 3 wherein R1 is 2-methyl, R2 is hydrogen, and R3 is5-methyl.
 17. A method according to claim 3 wherein R1 is 3-methyl, R2is hydrogen, and R3 is 4-methyl.
 18. A method according to claim 3wherein R1 is 3-methyl, R2 is hydrogen, and R3 is 5-methyl.
 19. A methodaccording to claim 3 wherein R1 is 2-chloro, R2 is hydrogen, and R3 is6-methyl.
 20. A method according to claim 3 wherein R1 is 2-methyl, R2is hydrogen, and R3 is 4-chloro.
 21. A method according to claim 3wherein R1 is 3-methyl, R2 is 4-chloro, and R3 is hydrogen.
 22. A methodaccording to claim 3 wherein R1 is 2-methyl, R2 is hydrogen, and R3 is4-fluoro.
 23. A method according to claim 3 wherein R1 is 2-chloro, R2is 4-chloro, and R3 is hydrogen.
 24. A method for lowering the serumlevel of triglycerides in animals including man, characterized inadministration to a host in need of such treatment a therapeuticallyeffective amount of a pharmaceutical preparation according to claim 1.25. A method for lowering the serum level of cholesterol in animalsincluding man, characterized in administration to a host in need of suchtreatment a therapeutically effective amount of a pharmaceuticalpreparation according to claim
 1. 26. A method for lowering the serumlevels of triglycerides and cholesterol in animals including man,comprising administration to a animal host in need of said treatment atherapeutically effective amount of a compound selected from the groupconsisting of